Summary: Neuromyelitis optica (NMO) is a rare but devastating inflammatory disorder of the central nervous system (CNS) that primarily affects the optic nerves and spinal cord. NMO was initially characterized as a subset of multiple sclerosis (MS), but is now considered a distinct disease. Currently, there are no FDA approved therapies for NMO. In fact, many MS therapies, most notably interferon-beta (IFN-?), worsens NMO. The limited therapies for NMO demonstrates that this disease has clear unmet needs in neurology. The goal of this project is to understand the immune pathways that contribute to disease activity in NMO. The aims of this proposal will address three connected but distinct issues that will have an impact NMO patients. Aim 1 will how determine how IFN-? signaling effects B-cells from patients with NMO. This will be achieved by CyTOF and transcriptomic analysis of B-cells from patients. Aim 2 will assess the direct interaction between B-cell subsets and T helper cells from NMO and healthy volunteers by utilizing cell culturing techniques. Aim 3 will utilize variations of experimental autoimmune encephalomyelitis model to understand how the B-cells cytokines effect TH17- induced neuro-autoimmune disease. The first two aims of this proposal will be a highly translation collaboration between Drs. Axtell, Lessard (autoimmune geneticist) and Pardo (the director of OMRF's MS Center of Excellence), and the Accelerated Cure Project (ACP). The clinical expertise and large patient population of the OMRF MS Center and the ACP will provide to this project will enable these aims to be accomplished. The third aim utilizes our strength in animal models of neuro-autoimmunity that will give insight into the biological mechanisms behind NMO. The combination of research on human subject and the mechanistic animal experiments outlined in this proposal have the potential to give deep insight into pathological processes that underlie and NMO.